三种先天性遗传病家系的疾病基因定位
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摘要
第一章一个先天性常染色体显形遗传副耳畸形家系致病基因的定位研究
目的定位先天性遗传性副耳畸形家系的疾病基因。方法对一个先天性副耳畸形的家系进行调查,对该家系进行了微卫星位点全基因组扫描。结果该家系的遗传模式为常染色体显性遗传,完全外显。通过两点连锁分析得到最大LOD值为4.20(D14S990 and D14S264,sita=0),通过单体型构建和多点连锁分析,将该致病基因锁定在14号染色体的D14S283和D14S297两位点(9.84cM)之间。结论我们将先天性副耳畸形疾病基因定位在14q11.2-q12区间内。这是迄今第一次对单纯性副耳畸形疾病基因的定位。
第二章一个先天性常染色体显形遗传白内障家系致病基因的定位研究和候选基因突变检测
目的定位和鉴别白内障致病基因。方法对一个先天性进行性板层核状白内障家系进行调查,对该家系的23个可疑患者进行了视光学检查,提取29位家庭成员的gDNA并进行连锁分析、单体型构建,对侯选疾病基因(BFSP1)进行突变检测。结果14个家庭成员被确诊患有先天性常染色体显性遗传板层核状白内障。连锁分析结果表明微卫星位点D20S904与该家系的致病基因紧密连锁,其LOD值为6.02(sita=0)。最后,该家系的致病基因被定位到20号染色体20p12.2-p11.23的D20S186至D20S912之间,该区间的长度为9.34MB。在此区间含括了BFSP1基因,但从我们对患者该基因编码区域的突变检测结果来看,没有发现有意义的突变。结论我们将一个先天性进行性板层核状白内障致病基因定位到20p11.23-p12.2.
第三章两个先天性性连锁遗传眼球震颤家系致病基因的定位研究
目的进一步缩小先天性传出性眼球震颤的致病基因在染色体的区间。方法对两个患有该病的中国大家系进行调查和确诊,并对该家系进行整个X染色体的基因组微卫星位点的长度扫描和连锁分析。结果在家系nys-01,发现了在X染色体长臂最大LOD值为8.55(DXS1047,sita=0)。在家系nys-02,几乎相同的位置发现了3.91的最大LOD值(DX1211和DXS1205,sita=0)。通过多点连锁分析和单体型构建,最终将该致病基因定位在X染色体微卫星标记DXS8044和DXS8041之间的7.1 cM。结论我们将先天性传出性眼球震颤致病基因定位到Xq25-q26.3的7.1个cM,并推测Xq26-q28的位置很可能存在两个眼球震颤的独立基因。
Chapter one Mapping the disease gene in a Congenital Accessory Auricular Anomaly family
Objective To map the gene for autosomal dominant accessory auricular anomaly(ADAAA).Methods A Chinese ADAAA family with 11 affected individuals was investigated.Linkage analysis with microsatellite markers spanning the whole human-genome in the family was carried out.Results The inheritance pattern of the ADAAA family was autosomal dominant with complete penetrance.Two-point linkage analysis revealed signifcant maximum LOD scores of 4.20(D14S990 and D14S264,sita=0)in the family.Haplotype construction and multipoint linkage analysis also confirmed the locus and defined the isolated ADAAA locus to a 9.84cM interval between the markers D14S283 and D14S297.Conclusions Our study assigned an isolated ADAAA locus to 14q11.2-q12.This is the first time ADAAA locus reported to date.
Objective To map and to identify the causal gene for autosomal dominant congenital cataract(ADCC)in a Chinese family. Methods A four-generation family with a history of congenital cataracts was investigated.Twenty-three members of the family were examined ophthalmologically.Blood samples were collected from twenty-nine family members for genetic linkage analysis.Two-point LOD scores were calculated.Multi-point linkage analysis and haplotype construction were performed to define the optimal cosegregating interval.Direct sequence analysis of the candidate gene,beaded filament structural protein 1, filensin(BFSP1)in the critical region was carried out.Results Fifteen family members were affected with autosomal dominant progressive congenital zonular nuclear cataract(ADPCZNC).The maximum two-point LOD Score of 6.02 was obtained for marker D20S904(=0). The cataract locus in this family was mapped to chromosome 20p11.23-p12.2,a 9.34 Mb(16.37 cM)interval between markers D20S 186 and D20S912.Although BFSP1 was in this critical region,no evidence was found that the condition in the family was caused by a BFSP1 mutation.Conclusions We have mapped the genetic locus of ADPCZNC to chromosome 20p11.23-p12.2 in an ADCC family.This is the first time ADPCZNC has been linked to this region.
Chapter three Mapping the disease gene in two Congenital motor nystagmus families
Objective In order to narrow down the candidate region and to identify the candidate gene for X-linked CMN.Methods Two families with CMN were investigated.Genotyping and linkage analysis were conducted in these two Chinese families.Results These two families were affected by X-linked CMN with incomplete penetrance. Two-point linkage analysis revealed significant maximum logarithm of odds(LOD)scores of 8.55(DXS10.47,sita=0)and 3.91(DXS1211 and DXS1205,=0)at the family nys-01 and the family nys-02 respectively. Haplotype construction and multipoint linkage analysis also confirmed the locus and refined the locus to a 7.1-cM interval between the markers DXS8044 and DXS8041 on chromosome Xq25-q26.3.Conclusion We have mapped the nystagemus gene to aninterval of 7.1 cM,at the location of Xq15-q26.3,such interval shares no overlap with previous Xq26-q27 locus.
目的定位先天性遗传性副耳畸形家系的疾病基因。方法对一个先天性副耳畸形的家系进行调查,对该家系进行了微卫星位点全基因组扫描。结果该家系的遗传模式为常染色体显性遗传,完全外显。通过两点连锁分析得到最大LOD值为4.20(D14S990 and D14S264,sita=0),通过单体型构建和多点连锁分析,将该致病基因锁定在14号染色体的D14S283和D14S297两位点(9.84cM)之间。结论我们将先天性副耳畸形疾病基因定位在14q11.2-q12区间内。这是迄今第一次对单纯性副耳畸形疾病基因的定位。
第二章一个先天性常染色体显形遗传白内障家系致病基因的定位研究和候选基因突变检测
目的定位和鉴别白内障致病基因。方法对一个先天性进行性板层核状白内障家系进行调查,对该家系的23个可疑患者进行了视光学检查,提取29位家庭成员的gDNA并进行连锁分析、单体型构建,对侯选疾病基因(BFSP1)进行突变检测。结果14个家庭成员被确诊患有先天性常染色体显性遗传板层核状白内障。连锁分析结果表明微卫星位点D20S904与该家系的致病基因紧密连锁,其LOD值为6.02(sita=0)。最后,该家系的致病基因被定位到20号染色体20p12.2-p11.23的D20S186至D20S912之间,该区间的长度为9.34MB。在此区间含括了BFSP1基因,但从我们对患者该基因编码区域的突变检测结果来看,没有发现有意义的突变。结论我们将一个先天性进行性板层核状白内障致病基因定位到20p11.23-p12.2.
第三章两个先天性性连锁遗传眼球震颤家系致病基因的定位研究
目的进一步缩小先天性传出性眼球震颤的致病基因在染色体的区间。方法对两个患有该病的中国大家系进行调查和确诊,并对该家系进行整个X染色体的基因组微卫星位点的长度扫描和连锁分析。结果在家系nys-01,发现了在X染色体长臂最大LOD值为8.55(DXS1047,sita=0)。在家系nys-02,几乎相同的位置发现了3.91的最大LOD值(DX1211和DXS1205,sita=0)。通过多点连锁分析和单体型构建,最终将该致病基因定位在X染色体微卫星标记DXS8044和DXS8041之间的7.1 cM。结论我们将先天性传出性眼球震颤致病基因定位到Xq25-q26.3的7.1个cM,并推测Xq26-q28的位置很可能存在两个眼球震颤的独立基因。
Chapter one Mapping the disease gene in a Congenital Accessory Auricular Anomaly family
Objective To map the gene for autosomal dominant accessory auricular anomaly(ADAAA).Methods A Chinese ADAAA family with 11 affected individuals was investigated.Linkage analysis with microsatellite markers spanning the whole human-genome in the family was carried out.Results The inheritance pattern of the ADAAA family was autosomal dominant with complete penetrance.Two-point linkage analysis revealed signifcant maximum LOD scores of 4.20(D14S990 and D14S264,sita=0)in the family.Haplotype construction and multipoint linkage analysis also confirmed the locus and defined the isolated ADAAA locus to a 9.84cM interval between the markers D14S283 and D14S297.Conclusions Our study assigned an isolated ADAAA locus to 14q11.2-q12.This is the first time ADAAA locus reported to date.
Objective To map and to identify the causal gene for autosomal dominant congenital cataract(ADCC)in a Chinese family. Methods A four-generation family with a history of congenital cataracts was investigated.Twenty-three members of the family were examined ophthalmologically.Blood samples were collected from twenty-nine family members for genetic linkage analysis.Two-point LOD scores were calculated.Multi-point linkage analysis and haplotype construction were performed to define the optimal cosegregating interval.Direct sequence analysis of the candidate gene,beaded filament structural protein 1, filensin(BFSP1)in the critical region was carried out.Results Fifteen family members were affected with autosomal dominant progressive congenital zonular nuclear cataract(ADPCZNC).The maximum two-point LOD Score of 6.02 was obtained for marker D20S904(=0). The cataract locus in this family was mapped to chromosome 20p11.23-p12.2,a 9.34 Mb(16.37 cM)interval between markers D20S 186 and D20S912.Although BFSP1 was in this critical region,no evidence was found that the condition in the family was caused by a BFSP1 mutation.Conclusions We have mapped the genetic locus of ADPCZNC to chromosome 20p11.23-p12.2 in an ADCC family.This is the first time ADPCZNC has been linked to this region.
Chapter three Mapping the disease gene in two Congenital motor nystagmus families
Objective In order to narrow down the candidate region and to identify the candidate gene for X-linked CMN.Methods Two families with CMN were investigated.Genotyping and linkage analysis were conducted in these two Chinese families.Results These two families were affected by X-linked CMN with incomplete penetrance. Two-point linkage analysis revealed significant maximum logarithm of odds(LOD)scores of 8.55(DXS10.47,sita=0)and 3.91(DXS1211 and DXS1205,=0)at the family nys-01 and the family nys-02 respectively. Haplotype construction and multipoint linkage analysis also confirmed the locus and refined the locus to a 7.1-cM interval between the markers DXS8044 and DXS8041 on chromosome Xq25-q26.3.Conclusion We have mapped the nystagemus gene to aninterval of 7.1 cM,at the location of Xq15-q26.3,such interval shares no overlap with previous Xq26-q27 locus.
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